This invention is in the field of drugs, pharmacology, and neurology. It relates to drugs that can protect the nervous and cardiovascular systems against conditions such as ischemia and hypoxia.
Ischemia refers to a condition of inadequate blood supply to an internal organ or portion of an organ. This condition is encountered during events such as stroke, heart attack, cardiac arrest, injury or trauma, shock, and internal hemorrhaging due to rupture of an aneurysm. Hypoxia refers to a state of inadequate oxygen supply to an organ. Hypoxia is a broader term and, as used herein, covers all forms of ischemia, since ischemia (inadequate blood flow) will lead directly to a hypoxia (an oxygen deficit) in any affected organ. Hypoxia can also occur despite normal blood flow, in conditions such as anemia, carbon monoxide poisoning, or asphyxia (which is used herein to include drowning, suffocation, perinatal asphyxia, etc).
Ischemia and hypoxia can lead to severe and permanent damage to the brain and central nervous system (CNS), even when they last only a few minutes. They are often fatal, and even when not, they can lead to widespread cell death in the central nervous system (CNS) causing crippling and irreversible damage such as paralysis, loss of speech or memory, and other effects that are physically, emotionally, and financially devastating.
In addition, "peripheral" hypoxia and/or ischemia can occur outside the CNS, in internal organs which are served by the sympathetic and parasympathetic nervous systems, and in tissue where blood flow is blocked or hindered by processes such as phlebitis, blood clots', shock, or loss of blood due to injury or hemorrhage.
Hypoxic/ischemic damage does not stop during "reperfusion," when oxygen or blood flow are restored to an organ or region of the brain; instead, the damage often increases sharply when oxygen is reintroduced after an anoxic period. During anoxia, certain metabolites and enzymes can accumulate which, when the anoxia ends, convert oxygen into a highly reactive free radical known as superoxide (O.sub.2.sup.-). Superoxide can attack any molecule, and it also promotes the release of iron ions from ferritin, which in turn promotes a process called "lipid peroxidation" which destroys cell membranes, as discussed in more detail below.
For more information on the cellular and molecular mechanisms involved in damage caused by hypoxia and/or ischemia, and on the various pharmaceutical approaches that are being studied in the hope of developing effective treatments for stroke, cardiac arrest, and other hypoxic or ischemic events, see Krause et al 1988. For additional background information on the structure, functioning, and biochemistry of the central and peripheral nervous systems, see Adelman 1987.